Doxazosin Attenuates Development of Testosterone Propionate-induced Prostate Growth by regulating TGF-β/Smad Signaling Pathway, Prostate-specific Antigen Expression and Reversing Epithelial-mesenchymal Transition in Mice and Stroma Cells

YiDan Li; BingHua Tu; ZiTong Wang; ZiChen Shao; ChenHao Fu; JianQiang Hua; ZiWen Zhang; Peng Zhang; Hui Sun; ChenYan Mao; Chi-Ming Liu

doi:10.2174/0118761429315125240919033502

Doxazosin Attenuates Development of Testosterone Propionate-induced Prostate Growth by regulating TGF-β/Smad Signaling Pathway, Prostate-specific Antigen Expression and Reversing Epithelial-mesenchymal Transition in Mice and Stroma Cells

Curr Mol Pharmacol. 2025 Jan 3. doi: 10.2174/0118761429315125240919033502. Online ahead of print.

Authors

YiDan Li^{1

2}, BingHua Tu¹, ZiTong Wang¹, ZiChen Shao^{1

2}, ChenHao Fu¹, JianQiang Hua¹, ZiWen Zhang¹, Peng Zhang¹, Hui Sun^{1

2}, ChenYan Mao¹, Chi-Ming Liu¹

Affiliations

¹ School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China.
² College of Chemistry and Bio-engineering, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China.

PMID: 39773046
DOI: 10.2174/0118761429315125240919033502

Abstract

Background: Finasteride and doxazosin are used for the treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Epithelial-mesenchymal transition (EMT) plays an important role in BPH, little is known about the growth inhibition and anti-fibrosis effects of doxazosin on the regulation of EMT and morphology in the prostate.

Objectives: The present study examined the effects of doxazosin on testosterone propionate (TP)-induced prostate growth in vivo and in vitro and its impact on the EMT and TGF-β/Smad signaling pathway.

Methods: Doxazosin (5 or 10 mg/kg) and finasteride (10 mg/kg) were administered orally for 28 days in TP-induced mice. The prostate index (prostate/body weight ratio), morphological characteristics and the protein expression of the prostate were examined. We further examined the effects of doxazosin and finasteride on the EMT and TGF-β/Smad signaling pathway in mice and in human prostate stroma cell (WPMY-1).

Results: The prostate wet weight, prostate index decreased after treatment. Doxazosin (5 or 10 mg/kg), finasteride (10 mg/kg) or a combination (doxazosin + finasteride) were shown to reverse the pathological and morphological characteristics of the prostate. Doxazosin and finasteride inhibited TP-induced prostate growth, EMT, and the TGF-β/Smad signaling pathway by downregulating the expression of TGF-β1, TGFBR2, p-Smad2/3, N-cadherin, vimentin, fibronectin and α-SMA, whereas expression of E-cadherin was increased after treatment with either doxazosin or finasteride. Doxazosin (1-50 μM) inhibited normal human prostate stroma cell growth (WPMY-1) after 48 h with or without testosterone treatment. Doxazosin also regulated the EMT and proteins related to the TGF-β/Smad signaling pathway in WPMY-1 cells after 24 h. Additionally, doxazosin decreased protein expression of the prostate specific antigen both in vivo and in vitro.

Conclusion: This study demonstrated that doxazosin inhibits prostate growth by regulating the EMT and TGF-β/Smad signaling pathways in the prostate This finding suggests that doxazosin has potential as a new signaling pathway for the treatment of BPH.

Keywords: Benign prostatic hyperplasia (BPH); Doxazosin; Epithelial-mesenchymal transition (EMT); Finasteride; TGF-β/Smad; α1- adrenoreceptor antagonist..